Benzodiazepine derivatives as RSV inhibitors
The present invention discloses compounds of Formula (I), or pharmaceutically acceptable salts, esters, or prodrugs thereof: which inhibit Respiratory Syncytial Virus (RSV). The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject suffering from RSV infection. The invention also relates to methods of treating an RSV infection in a subject by administering a pharmaceutical composition comprising the compounds of the present invention.
1. A compound represented by Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from the group consisting of:
1) Hydrogen;
2) Halogen;
3) CN;
4) Optionally substituted —C 1 -C 8 alkyl; and
5) Optionally substituted —C 1 -C 8 alkyl —O—R 11 ;
R 2 and R 5 are each independently selected from the group consisting of:
1) Hydrogen; and
2) Optionally substituted —C 1 -C 8 alkyl;
A is selected from the group consisting of:
1) Optionally substituted —C 3 -C 12 cycloalkyl;
2) Optionally substituted —C 3 -C 12 cycloalkenyl;
3) Optionally substituted aryl; and
4) Optionally substituted heteroaryl
R 3 is hydrogen or R 11 ;
R 4 is selected from the group consisting of:
1) Optionally substituted —C 3 -C 12 cycloalkyl;
2) Optionally substituted —C 3 -C 12 cycloalkenyl;
3) Optionally substituted 3- to 12-membered heterocyclic;
4) Optionally substituted aryl;
5) Optionally substituted heteroaryl;
6) Optionally substituted aryl-O—;
7) Optionally substituted heteroaryl-O;
8) Optionally substituted aryl-C 1 -C 4 -alkyl; and
9) Optionally substituted heteroaryl-C 1 -C 4 -alkyl;
wherein R 4 is optionally substituted with 1 to 3 substituents independently selected from halo, —CH 3 , —CF 3 , —OCF 3 , —CN, —NH 2 , —OH, —CH 2 N(CH 3 ) 2 , —C(O)CH 3 , —NH—(C 1 -C 6 )alkyl, —NH—(C 1 -C 6 )alkyl-(C 1 -C 6 )alkoxy, —SO 2 —(C 1 -C 6 )alkyl, —SO 2 —NH—(C 1 -C 6 )alkyl, —NH—SO 2 —(C 1 -C 6 )alkyl, 3- to 12-membered heterocyclic, aryl, heteroaryl, C 1 -C 8 -alkyl, C 2 -C 8 -alkenyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 -cycloalkenyl, C 1 -C 8 -alkoxy, CH 3 OCH 2 —, CH 3 OCH 2 CH 2 O—,
each R 6 is independently selected from hydrogen, halogen, hydroxyl, protected hydroxyl, cyano, amino, protected amino, nitro, optionally substituted —C 1 -C 8 alkyl, optionally substituted —C 1 -C 8 alkoxy, optionally substituted —NHC 1 -C 8 alkyl, optionally substituted —S—(—C 1 -C 8 alkyl), optionally substituted —SO 2 —(—C 1 -C 8 alkyl), -optionally substituted —SO 2 —NH—(—C 1 -C 8 alkyl), optionally substituted —NH—SO 2 —(—C 1 -C 8 alkyl), —CO 2 R 12 , —NR 13 R 14 , and —CO—NR 13 R 14 ;
R 11 and R 12 are each independently selected from the group consisting of:
1) Optionally substituted —C 1 -C 8 alkyl;
2) Optionally substituted —C 2 -C 8 alkenyl;
3) Optionally substituted —C 2 -C 8 alkynyl;
4) Optionally substituted —C 3 -C 8 cycloalkyl;
5) Optionally substituted —C 3 -C 8 cycloalkenyl;
6) Optionally substituted 3- to 8-membered heterocyclic;
7) Optionally substituted aryl; and
8) Optionally substituted heteroaryl;
R 13 and R 14 are each independently selected from hydrogen, optionally substituted —C 1 -C 8 -alkyl, optionally substituted —C 2 -C 8 -alkenyl, optionally substituted —C 2 -C 8 -alkynyl; optionally substituted —C 3 -C 8 -cycloalkyl, —C(O)R 12 , —S(O) 2 R 12 , and —S(O) 2 NHR 12 , and optionally substituted —C 1 -C 8 -alkoxy; alternatively, R 13 and R 14 are taken together with the nitrogen atom to which they are attached to form a heterocyclic ring; and n is 0, 1, 2, 3 or 4; and
wherein each substituted R 1 , R 2 , R 5 , R 6 , R 11 , R 12 , R 13 , R 14 and A is substituted by one or more substituents selected from deuterium, tritium, —F, —Cl, —Br, —I, —OH, protected hydroxy, —NO 2 , —CN, —NH 2 , —N 3 , protected amino, alkoxy, thioalkoxy, oxo, thioxo, —C 1 -C 12 -alkyl, —C 2 -C 12 -alkenyl, —C 2 -C 12 -alkynyl, —C 3 -C 12 -cycloalkyl-halo-C 1 -C 12 -alkyl, -halo-C 2 -C 12 -alkenyl, -halo-C 2 -C 12 -alkynyl, -halo-C 3 -C 12 -cycloalkyl, —NH—C 1 -C 12 -alkyl, —NH—C 2 -C 12 -alkenyl, —NH—C 2 -C 12 -alkynyl, —NH—C 3 -C 12 -cycloalkyl, —NH-aryl, —NH-heteroaryl, —NH-heterocyclic, -dialkylamino, -diarylamino, -diheteroarylamino, —O—C 1 -C 12 -alkyl, —O—C 2 -C 12 -alkenyl, —O—C 2 -C 12 -alkynyl, —O—C 3 -C 12 -cycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocyclic, —C(O)—C 1 -C 12 -alkyl, —C(O)—C 2 -C 12 -alkenyl, —C(O)—C 2 -C 12 -alkynyl, —C(O)—C 3 -C 12 -cycloalkyl, —C(O)-aryl, —C(O)-heteroaryl, —C(O)-heterocyclic, —CONH 2 , —CONH—C 1 -C 12 -alkyl, —CONH—C 2 -C 12 -alkenyl, —CONH—C 2 -C 12 -alkynyl, —CONH—C 3 -C 12 -cycloalkyl, —CONH-aryl, —CONH-heteroaryl, —CONH-heterocyclic, —OCO 2 —C 1 -C 12 -alkyl, —OCO 2 —C 2 -C 12 -alkenyl, —OCO 2 —C 2 -C 12 -alkynyl, —OCO 2 —C 3 -C 12 -cycloalkyl, —OCO 2 -aryl, —OCO 2 -heteroaryl, —OCO 2 -heterocyclic, —OCONH 2 , —OCONH—C 1 -C 12 -alkyl, —OCONH—C 2 -C 12 -alkenyl, —OCONH—C 2 -C 12 -alkynyl, —OCONH—C 3 -C 12 -cycloalkyl, —OCONH-aryl, —OCONH-heteroaryl, —OCONH-heterocyclic, —NHC(O)—C 1 -C 12 -alkyl, —NHC(O)—C 2 -C 12 -alkenyl, —NHC(O)—C 2 -C 12 -alkynyl, —NHC(O)—C 3 -C 12 -cycloalkyl, —NHC(O)-aryl, —NHC(O)-heteroaryl, —NHC(O)-heterocyclic, —NHCO 2 —C 1 -C 12 -alkyl, —NHCO 2 —C 2 -C 12 -alkenyl, —NHCO 2 —C 2 -C 12 -alkynyl, —NHCO 2 —C 3 -C 12 -cycloalkyl, —NHCO 2 -aryl, —NHCO 2 -heteroaryl, —NHCO 2 -heterocyclic, —NHC(O)NH 2 , —NHC(O)NH—C 1 -C 12 -alkyl, —NHC(O)NH—C 2 -C 12 -alkenyl, —NHC(O)NH—C 2 -C 12 -alkynyl, —NHC(O)NH—C 3 -C 12 -cycloalkyl, —NHC(O)NH-aryl, —NHC(O)NH-heteroaryl, —NHC(O)NH-heterocyclic, NHC(S)NH 2 , —NHC(S)NH—C 1 -C 12 -alkyl, —NHC(S)NH—C 2 -C 12 -alkenyl, —NHC(S)NH—C 2 -C 12 -alkynyl, —NHC(S)NH—C 3 -C 12 -cycloalkyl, —NHC(S)NH-aryl, —NHC(S)NH-heteroaryl, —NHC(S)NH-heterocyclic, —NHC(NH)NH 2 , —NHC(NH)NH—C 1 -C 12 -alkyl, —NHC(NH)NH—C 2 -C 12 -alkenyl, —NHC(NH)NH—C 2 -C 12 -alkynyl, —NHC(NH)NH—C 3 -C 12 -cycloalkyl, —NHC(NH)NH-aryl, —NHC(NH)NH-heteroaryl, —NHC(NH)NH-heterocyclic, —NHC(NH)—C 1 -C 12 -alkyl, —NHC(NH)—C 2 -C 12 -alkenyl, —NHC(NH)—C 2 -C 12 -alkynyl, —NHC(NH)—C 3 -C 12 -cycloalkyl, —NHC(NH)-aryl, —NHC(NH)-heteroaryl, —NHC(NH)-heterocyclic, —C(NH)NH—C 1 -C 12 -alkyl, —C(NH)NH—C 2 -C 12 -alkenyl, —C(NH)NH—C 2 -C 12 -alkynyl, —C(NH)NH—C 3 -C 12 -cycloalkyl, —C(NH)NH-aryl, —C(NH)NH-heteroaryl, —C(NH)NH-heterocyclic, —S(O)—C 1 -C 12 -alkyl, —S(O)—C 2 -C 12 -alkenyl, —S(O)—C 2 -C 12 -alkynyl, —S(O)—C 3 -C 12 -cycloalkyl, —S(O)-aryl, —S(O)-heteroaryl, —S(O)-heterocyclic —SO 2 NH 2 , —SO 2 NH—C 1 -C 12 -alkyl, —SO 2 NH—C 2 -C 12 -alkenyl, —SO 2 NH—C 2 -C 12 -alkynyl, —SO 2 NH—C 3 -C 12 -cycloalkyl, —SO 2 NH-aryl, —SO 2 NH-heteroaryl, —SO 2 NH-heterocyclic, —NHSO 2 —C 1 -C 12 -alkyl, —NHSO 2 —C 2 -C 12 -alkenyl, —NHSO 2 —C 2 -C 12 -alkynyl, —NHSO 2 —C 3 -C 12 -cycloalkyl, —NHSO 2 -aryl, —NHSO 2 -heteroaryl, —NHSO 2 -heterocyclic, —CH 2 NH 2 , —CH 2 SO 2 CH 3 , -aryl, -arylalkyl, -heteroaryl, -heteroarylalkyl, -heterocyclic, —C 3 -C 12 -cycloalkyl, polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, —SH, —S—C 1 -C 12 -alkyl, —S—C 2 -C 12 -alkenyl, —S—C 2 -C 12 -alkynyl, —S—C 3 -C 12 -cycloalkyl, —S-aryl, —S-heteroaryl, —S-heterocyclic, methylthiomethyl, or -L′-R′, wherein L′ is C 1 -C 6 alkylene, C 2 -C 6 alkenylene or C 2 -C 6 alkynylene, and R′ is aryl, heteroaryl, heterocyclic, C 3 -C 12 cycloalkyl or C 3 -C 12 cycloalkenyl.
2. The compound of claim 1 , wherein the compound is represented by Formula (Ia) or Formula (Ib):
3. The compound of claim 1 , wherein A is selected from one of the following by removal of two hydrogen atoms:
wherein each of the above shown is optionally substituted when possible.
4. The compound of claim 1 , wherein R 4 is selected from one of the following by removal of one hydrogen atom:
wherein each of the above shown is optionally substituted.
5. The compound of claim 1 , wherein R 4 is substituted by one to three substituents independently selected from:
halo, —CH 3 , —CF 3 , —OCF 3 , —CN, —NH 2 , —OH, —CH 2 N(CH 3 ) 2 , —C(O)CH 3 , —NH(C 1 -C 6 )alkyl, —NH—(C 1 -C 6 )alkyl-(C 1 -C 6 )alkoxy, —SO 2 —(C 1 -C 6 )alkyl, —SO 2 —NH—(C 1 -C 6 )alkyl, —NH—SO 2 —(C 1 -C 6 )alkyl, 3 to 12-membered heterocyclic, aryl, heteroaryl, —C 1 -C 8 -alkyl, —C 1 -C 8 -alkenyl, —C 3 -C 8 -cycloalkyl, —C 3 -C 8 -cycloalkenyl, and —C 1 -C 8 -alkoxy.
6. The compound of claim 1 wherein R 4 is substituted by one, two or three substituents selected from: CH 3 , CN, fluoro, chloro, CH 3 O—, CH 3 C(O)—, CH 3 OCH 2 —, CH 3 OCH 2 CH 2 O—, —CF 3 , CF 3 O—,
7. The compound of claim 1 , represented by Formula IIa-1, IIa-2, IIb-1, or IIb-2,
or a pharmaceutically acceptable salt thereof.
8. The compound of claim 1 , represented by Formula IV-1, IV-2, IV-3, or IV-4,
or a pharmaceutically acceptable salt thereof.
9. The compound of claim 1 , represented by Formula V-1, V-2, V-3, or V-4,
or a pharmaceutically acceptable salt thereof.
10. A compound selected from the compounds set forth below or a pharmaceutically acceptable salt thereof:
Compound
Structure
1
2
3
4
5
6
7a
7b
8
9
10a
10b
11
12
13
14
15
16
17
19
20
21
22
23
24
25
26
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32
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51
52
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58
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60
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75
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77
80
81
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85
86
87
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89
90
91
92
93
94
95
96
97
107
108
109
110
111
112
113
114
115
116
117
118
119
120
121
122
123
124a
124b
125a
125b
126a
126b
127
128
129
130
131
132
133
134
135
136
137
138
139
140
141
142
143
144
145
146
147
148
149
150
151
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154
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156
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160
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162
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175
176
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181
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185
186
187
195
196
197
198
199
200
201
202
204
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207
208
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210
211
212
214
215
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217
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223
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228
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234
235
236
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242
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293
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312
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315
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321
322
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324
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328
329
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331
332
333
334
335
336
337
338
339
340
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342
343
344
345
346
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349
350
351
352
353
354
355a
355b
356
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358
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362
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401
402
403
404
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407
408
409
410
411
412
413
414
415
416
417
418
419
420
421
422
423
424
425
426
427
428
429
430
431
432
433
434
435
436
437
438
439
440
441
442
443
444
445
446
447
448
449
450
451
452
453
454
455
456
457
458
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501
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510
511
512
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514
515
516
517
518
11. A pharmaceutical composition, comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
12. A method of treating an RSV infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or a combination of compounds of claim 1 .
13. The method of claim 12 , further comprising administering to the subject an additional therapeutic agent selected from steroid anti-inflammatory compounds and nonsteroid anti-inflammatory compounds.
14. The method of claim 12 , wherein the subject has concomitant RSV and influenza infections, said method further comprising administering to the subject an anti-influenza compound.
15. The method of claim 13 , wherein the compound and the additional therapeutic agent are co-formulated.
16. The compound of claim 1 , represented by Formula (VIa-1), (VIa-2), (VIa-3), (VIa-4), (VIb-1), (VIb-2), (VIb-3), or (VIb-4,)
or a pharmaceutically acceptable salt thereof,
wherein
R 4 is selected from the groups below,
each of which is optionally substituted with one to three substituents independently selected from halo, —CH 3 , —CF 3 , —OCF 3 , —CN, —NH 2 , —OH, —CH 2 N(CH 3 ) 2 , —C(O)CH 3 , —NH—(C 1 -C 6 )alkyl, —NH—(C 1 -C 6 )alkyl-(C 1 -C 6 )alkoxy, —SO 2 —(C 1 -C 6 )alkyl, —SO 2 —NH—(C 1 -C 6 )alkyl, —NH—SO 2 —(C 1 -C 6 )alkyl, 3- to 12-membered heterocyclic, aryl, heteroaryl, —C 1 -C 8 -alkyl, —C 1 -C 8 -alkenyl, —C 3 -C 8 -cycloalkyl, —C 3 -C 8 -cycloalkenyl, and —C 1 -C 8 -alkoxy.
17. The compound of claim 1 , represented by Formula (VIa-1), (VIa-2), (VIa-3), (VIa-4), (VIb-1), (VIb-2), (VIb-3), or (VIb-4,)
or a pharmaceutically acceptable salt thereof,
wherein
R 4 is selected from the groups below,
each of which is optionally substituted with one to three substituents independently selected from CH 3 , CN, fluoro, chloro, CH 3 O—, CH 3 C(O)—, CH 3 OCH 2 —, CH 3 OCH 2 CH 2 O—, —CF 3 , CF 3 O—,
18. A compound represented by Formula (VIa-1), (VIa-2), (VIa-3), (VIa-4), (VIb-1), (VIb-2), (VIb-3), or (VIb-4,)
or a pharmaceutically acceptable salt thereof,
wherein
R 4 is selected from the groups in the table below,